Mitochondrial Dysfunction and Acute Fatty Liver of Pregnancy

Abstract

The liver is one of the richest organs in mitochondria, serving as a hub for key metabolic pathways such as β-oxidation, the tricarboxylic acid (TCA) cycle, ketogenesis, respiratory activity, and adenosine triphosphate (ATP) synthesis, all of which provide metabolic energy for the entire body. Mitochondrial dysfunction has been linked to subcellular organelle dysfunction in liver diseases, particularly fatty liver disease. Acute fatty liver of pregnancy (AFLP) is a life-threatening liver disorder unique to pregnancy, which can result in serious maternal and fetal complications, including death. Pregnant mothers with this disease require early detection, prompt delivery, and supportive maternal care. AFLP was considered a mysterious illness and though its pathogenesis has not been fully elucidated, molecular research over the past two decades has linked AFLP to mitochondrial dysfunction and defects in fetal fatty-acid oxidation (FAO). Due to deficient placental and fetal FAO, harmful 3-hydroxy fatty acid metabolites accumulate in the maternal circulation, causing oxidative stress and microvesicular fatty infiltration of the liver, resulting in AFLP. In this review, we provide an overview of AFLP and mitochondrial FAO followed by discussion of how altered mitochondrial function plays an important role in the pathogenesis of AFLP.

Keywords: acute fatty liver of pregnancy; liver; long chain 3-hydroxyacyl Co-A; mitochondrial dysfunction; mitochondrial trifunctional protein; β-oxidation.

Figure 1

A schematic representation of free fatty acid transport to mitochondria. TG: Triglyceride; FFA: Free fatty acid.

Figure 2

The role of mitochondria in fatty-acid oxidation and energy production. Excessive electron leakage causes excessive ROS generation and cellular injury. FFA: Free fatty acid; NADH: Nicotinamide adenine dinucleotide; FADH: Flavin adenine dinucleotide; ROS: Reactive oxygen species; ETC: Electron transport chain; MOM: Mitochondrial outer membrane; MIM: Mitochondrial inner membrane; ADP: Adenosine diphosphate; e: electrons; ATP: Adenosine triphosphate; TNF-α: Tumor necrosis factor-α; NF-KB: Nuclear factor-KB; IL: Interleukin; MAPKs: Mitogen activated protein kinases; JNK: c-jun N terminal kinase; AMPK: AMP-activated protein kinase.

Figure 3

A schematic representation of possible mechanisms leading to the development of maternal AFLP associated with fetal LCHAD deficiency. MTP: Mitochondrial Trifunctional Protein; LCHAD: Long chain acyl-CoA dehydrogenase.